# Identification and validation of key PANoptosis-related genes via integrative machine learning and single-cell sequencing in AILI

## TL;DR

This study identifies Cdkn1a and Pdk1 as key genes linked to PANoptosis in acetaminophen-induced liver injury, offering new insights into liver disease mechanisms and potential biomarkers.

## Contribution

The novel contribution is the identification of Cdkn1a and Pdk1 as PANoptosis-related biomarkers in AILI using integrative machine learning and single-cell sequencing.

## Key findings

- Cdkn1a and Pdk1 are key PANoptosis-related genes with high diagnostic potential for AILI.
- Pdk1 knockdown in vivo worsens AILI by promoting PANoptosis.
- Immune cell interactions are linked to Cdkn1a and Pdk1 expression patterns.

## Abstract

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury and acute liver failure. PANoptosis, a recently defined form of programmed cell death, is closely linked to immune regulation; however, its role in APAP-induced liver injury (AILI) remains unclear. Here, we aimed to identify PANoptosis-related biomarkers and elucidate their functions in AILI. By integrating bulk RNA-seq, weighted gene co-expression network analysis, machine learning, and single-cell RNA-seq, we identified Cdkn1a and Pdk1 as key PANoptosis-related genes with high diagnostic potential. Immune infiltration analyses revealed significant associations between these genes and multiple immune cell populations. Single-cell analysis demonstrated cell-type-specific expression patterns and enhanced signaling between hepatocytes and macrophages, as well as between T cells and neutrophils. Experimental validation confirmed that Cdkn1a and Pdk1 correlated with liver injury severity, and in vivo knockdown of Pdk1 exacerbated AILI by promoting PANoptosis. Collectively, our findings identify Cdkn1a and Pdk1 as promising biomarkers in AILI.

•PANoptosis-related genes are highly associated with AILI•Cdkn1a and Pdk1 exhibit high diagnostic value for AILI•Cdkn1a and Pdk1 expression correlates with AILI severity•Knockdown of Pdk1 exacerbates AILI by promoting PANoptosis in vivo

PANoptosis-related genes are highly associated with AILI

Cdkn1a and Pdk1 exhibit high diagnostic value for AILI

Cdkn1a and Pdk1 expression correlates with AILI severity

Knockdown of Pdk1 exacerbates AILI by promoting PANoptosis in vivo

Immunology; Molecular genetics; Cell biology